Influenza viruses are etiological agents of deadly flu that continue to pose global health threats and have caused global pandemics that killed millions of people worldwide. The global crisis posed by the emergence of the avian H5N1 influenza virus provides testament to the challenges of defending against a deadly virus that is unpredictable and ever changing. As the human death toll from the bird flu outbreaks continues to increase, the world is moving closer to a potential influenza pandemic. With a reported case fatality over 50%, an influenza pandemic by a highly transmissible strain of avian H5N1 influenza virus could potentially kill millions of people worldwide.
There are a number of commercially available antiviral drugs which can be considered as the first line of defense against seasonal or avian influenza infections. There are two conventional influenza drugs, namely amantadine and rimantadine, which have been used clinically to reduce the severity and duration of seasonal flu. These compounds arc M2 ion-channel blocking adamantine derivatives that work by interfering with viral uncoating inside the cells. In recent years, good advances have been made in the development of anti-influenza drugs, particularly the development of neuramidase inhibitors, namely Tamiflu™ (Zanamivir) [4-acetamido-5-amino-3-(1-ethylpropoxyl)-1-cyclohexene-1-carboxylic acid ethyl ester (invented by Gilead Sciences and marketed by Roche AG, and Relenza™ (Oseltamivir) (4-guanidino-Neu5Ac2en) (marketed by Glaxo-SmithKline). Neuraminidase is one of the glycoproteins present on the virus surface, and it is an enzyme that cleaves sialic acid residues from the receptors for the virus. The inhibition of this enzyme by Tamiflu™ and Relenza™ stops the spread of this virus and effectively suppresses infection.
One of the greatest challenges with current stockpiling of antiviral drugs as part of pandemic planning or bioterrorism defense is high level of drug-resistance of influenza viruses. Most seasonal human influenza strains (H3N2) are resistant to amantadine and rimantadine, thereby limiting their usefulness against seasonal influenza. When the distribution of genetic mutations associated with resistance of avian H5N1 influenza virus to amantadine and rimantadine was determined, it was found that more than 95% of isolates of avian H5N1 influenza from Thailand and Vietnam contained resistance mutations to these drugs. While many western nations are stockpiling drugs such as Tamiflu™ as part of the pandemic preparedness plan, there is a growing concern that the circulating avian flu virus may be resistant to Tamiflu™. Significant number of the avian flu clinical isolates from hard-hit areas in Vietnam had developed resistance to Tamiflu™. As global fears of a pandemic grow, the use of neuraminidase inhibitors against seasonal influenza has been shown to significantly increase, and this will lead to corresponding incidence of drug-resistance to these drugs. Another challenge posed by stockpiling of Tamiflu™ is that for the drug to be effective, it has to be given within 48 hours after exposure. Once the symptoms of infection appear the therapeutic efficacy of the drugs decreases dramatically. To better defend against influenza, whether seasonal and/or pandemic, there are compelling reasons to develop novel drugs or drug combinations that are safe, effective and less likely to give rise to drug-resistance.
Poly ICLC is a synthetic, double-stranded RNA (ds RNA) comprised of polyriboinosinic-polyribocytidylic (I:C) acid stabilized with poly-L-lysine and carboxymethylcellulose. Poly ICLC is a potent immunomodulating agent (Wong 2007). Liposome encapsulated Poly ICLC (LE Poly ICLC) was found to be a broadly effective prophylactic against a number of seasonal and avian influenza viruses in pre-exposure therapies (Wong 2007). LE Poly ICLC was also found to provide high level of protection in mice against highly pathogenic H5N1 avian influenza A virus. The window of protection provided by LE Poly ICLC was determined by pre-treating mice with 2 intranasal (IN) doses (1 mg/kg/dose) of LE Poly ICLC at day 1 to day 20 prior to infection with 10 LD50 of influenza A/PR/8/34 virus. Although LE Poly ICLC when given to experimental animals in a pre-exposure prophylactic mode has been shown to provide complete protection against a number of influenza virus strains, including H5N1, H3N2 and H1N1 subtypes, its efficacy when administered in a post-exposure treatment mode after viral infection remains to be determined.
Ribonucleotide oligonucleotides (RNOs) are known to provide antiviral protection, including protection against influenza A viruses. Liposome encapsulated RNOs have been shown to be effective in the post-exposure treatment of mice infected with influenza A virus (Wong 2003). Other antisense oligonucleotides useful against influenza virus infections are know (Mizuta 1999; Zhang 2010).
There is a need in the art for new therapies against viral infections, in particular against influenza A virus.